Additional Data Submitted to BLA following FDA
Request, PDUFA Action Date Extended to April 27, 2017
BioMarin Pharmaceutical Inc. (Nasdaq:BMRN) today announced a
program update for cerliponase alfa, a recombinant human
tripeptidyl peptidase 1 (rhTPP1) to treat children with CLN2
disease, a form of Batten disease. CLN2 disease is a rapidly
progressing, fatal neurodegenerative disease with no approved
treatments, where the majority of affected children lose their
ability to walk and talk by approximately six years of age.
After 81 weeks, patients treated with cerliponase alfa continue to
have motor-language (ML) scores representing substantial
attenuation of disease progression compared to natural
history. These data are consistent with the data at 48 weeks
submitted with the original Biologics License Application (BLA),
and demonstrate durable and consistent treatment response.
During their initial review of the BLA, the U.S. Food and Drug
Administration (FDA) requested an updated efficacy data cut from
the ongoing extension study, which the company provided. The
FDA designated this submission as a major amendment to the
application, thus extending the PDUFA action date by three months
to April 27, 2017.
FDA has not communicated their rationale for declaring this
submission a major amendment. This review division has
extended PDUFA timelines for breakthrough products in the
past. The Agency has advised that they plan to hold an
advisory committee meeting at a date to be confirmed per their
usual practice of notification in the Federal Register.
The additional data continue to show that the Hamburg Motor +
Language CLN2 scores1 of a majority of treated patients are
stable. Natural history of the disease shows an average of
2.1 points of decline over 48 weeks and an expected 3 points of
decline over 81 weeks.2 Updated analysis of the estimated
rate of decline including approximately 8 months of additional data
continues to show substantial attenuation of disease progression
with cerliponase alfa treatment. The mean (95% Confidence Interval)
rate of decline of the Motor Language score in points per 48 weeks
for the Intent to Treat (ITT) population (n = 23) as of 03 June
2016 was 0.32 (0.13, 0.52) (p < 0.0001 compared to a 2-point
decline derived from available natural history), which was based on
81 weeks of treatment. This rate is improved from the
corresponding rate of decline reported in the original BLA of 0.48
(0.16, 0.81), which was based on 48 weeks of treatment.
The primary analysis, agreed to with FDA, is a
responder analysis where patients with decline in CLN2 score (<2
points over 48 weeks) are defined as responders. The response
rate at 81 weeks (< 2 point decline in CLN2 score) remained 87%,
as reported in the original BLA.
Consistent with previous data cuts, cerliponase
alfa administered via intracerebroventricular infusion every 14
days was well tolerated, and no patients discontinued treatment due
to adverse events (AEs). Most AEs were Grade 1 or 2, and the
majority are consistent with severe, chronic neurologic disease in
pediatric patients. The most common events associated with
treatment included: pyrexia, hypersensitivity, seizure,
epilepsy, vomiting and headache. No new safety signals were
observed.
“We continue to work with the Agency to respond to their
requests regarding available natural history data, clinical scales
used to characterize the treatment effect, and durability of
response,” said Hank Fuchs, M.D., Chief Medical Officer of
BioMarin. “We believe that the continued maintenance of
benefit, as well as the supporting responder analysis provides
substantial evidence of effectiveness. We look forward to receiving
further feedback from the Agency as the review progresses.”
Children with CLN2 disease typically begin to present symptoms
between the ages of two and four, with the majority of affected
children losing their ability to walk and talk by approximately six
years of age. Initial symptoms can include language delay and
seizures, followed by movement disorders, motor deterioration,
dementia and blindness. During the later stages of the disease,
feeding and tending to everyday needs become very difficult, and
death often occurs between 8 and 12 years of age. BioMarin
estimates the incidence of CLN2 disease is approximately one in
200,000 with approximately 1,200 to 1,600 children in BioMarin’s
commercial territories.
Marketing Applications
The FDA and European Medicines Agency (EMA) granted cerliponase
alfa Orphan Drug Designation. In addition, the FDA granted
cerliponase alfa Priority Review Status and Breakthrough Therapy
designation.
BioMarin has submitted a Marketing Authorization Application
(MAA) to the EMA for cerliponase alfa, and it is undergoing
validation at the Agency, an update is expected shortly. The
EMA has granted BioMarin's request for accelerated
assessment. Accelerated assessments are granted on the
grounds that a product may satisfy an unmet medical need and is of
major interest from the point of view of therapeutic innovation and
public health. Accelerated assessment has the potential to
shorten EMA's review procedure. However, at any time during
the MAA assessment, the EMA may decide to continue the assessment
under standard assessment timelines, and most applications that
initially qualify for accelerated assessment are ultimately
reviewed on a standard timeline.
Study Design
The study is an open-label, dose-escalation study in patients
with CLN2 disease between three and 16 years of age. The
primary objectives are to evaluate the safety and tolerability of
ICV-administered cerliponase alfa and to evaluate effectiveness
using a CLN2 disease-specific rating scale score in comparison with
natural history data after 48 weeks of treatment. The study
enrolled 24 subjects at five clinical sites. Subjects were
administered a stable dose of cerliponase alfa (300 mg by ICV
infusion every 14 days) for at least 48 weeks. After 48
weeks, all subjects enrolled into an extension study which remains
ongoing.
Early Access Program
BioMarin has implemented an early access (compassionate use)
program as planned to provide experimental drug for additional CLN2
patients prior to obtaining marketing approval. The program
is limited in scope and number of participants, and is being
conducted under a protocol. The program initially is being
conducted at centers that have participated in the cerliponase alfa
study. The program began in August 2016 in Hamburg, Germany
and Columbus, OH, U.S.A. We continue to work on opening the
other sites, while adhering to specific legal and regulatory
procedures for each country. In order to assure fairness in
inclusion, enrollment decisions will be made independent of
BioMarin. In addition, the identities of participants are
confidential to protect the privacy of the patients and
families.
About Cerliponase Alfa
Cerliponase alfa is a recombinant form of human TPP1, the enzyme
deficient in patients with CLN2 disease. It is an enzyme
replacement therapy designed to restore TPP1 enzyme activity and
break down the storage materials that cause CLN2 disease. In
order to reach the cells of the brain and central nervous system,
the treatment is delivered directly to the fluid surrounding the
brain (cerebrospinal fluid) using BioMarin’s patented
technology.
For additional information regarding the investigational product
cerliponase alfa, please contact BioMarin Medical Information at
medinfo@bmrn.com.
About CLN2 Disease
The neuronal ceroid lipofuscinoses (NCLs) are a heterogeneous
group of lysosomal storage disorders that includes the autosomal
recessive neurodegenerative disorder CLN2 disease. CLN2 disease is
caused by mutations in the TPP1/CLN2 gene resulting in deficient
activity of the enzyme tripeptidyl peptidase 1 (TPP1). In the
absence of TPP1, lysosomal storage materials normally metabolized
by this enzyme accumulate in many organs, particularly in the brain
and retina. Buildup of these storage materials in the cells of the
nervous system contribute to the progressive and relentless
neurodegeneration which manifests as loss of cognitive, motor, and
visual functions. Disease progression is rapid. The onset of
symptoms is typically between ages two and four. Patients typically
present initially with language delay and seizures, followed by
movement disorders, motor deterioration, dementia, blindness and
early death. During the later stages of the disease, feeding and
tending to everyday needs become very difficult and death typically
occurs between ten and 16 years of age.
There is no approved treatment that can prevent, stop, or
reverse CLN2 disease. Symptomatic care to treat the symptoms of the
disease, prevent and treat complications, and attempt to preserve
quality of life is the only available treatment options for
patients with this rare disease.
About BioMarin
BioMarin is a global biotechnology company that develops and
commercializes innovative therapies for patients with serious and
life-threatening rare and ultra-rare genetic diseases. The
company's portfolio consists of five commercialized products and
multiple clinical and pre-clinical product candidates.
For additional information, please visit www.BMRN.com.
Information on BioMarin's website is not incorporated by reference
into this press release.
Forward-Looking Statement
This press release contains forward-looking statements about the
business prospects of BioMarin Pharmaceutical Inc., including,
without limitation, statements about: BioMarin's development
programs for cerliponase alfa generally, and specifically about
regulatory filings for commercial approval of the product candidate
the results of the Phase 1/2 pivotal trial and an ongoing extension
study of cerliponase alfa. These forward-looking statements are
predictions and involve risks and uncertainties such that actual
results may differ materially from these statements. These risks
and uncertainties include, among others: results of current and
planned clinical trials of cerliponase alfa; the content and timing
of decisions by the U.S. Food and Drug Administration, the European
Medicines Agency and other regulatory authorities; our ability to
manufacture sufficient quantities of cerliponase alfa for clinical
trials, commercial launch and other preapproval requirements; and
those factors detailed in BioMarin's filings with the Securities
and Exchange Commission, including, without limitation, the factors
contained under the caption "Risk Factors" in BioMarin's 2015
Annual Report on Form 10-K, as amended, and the factors contained
in BioMarin's reports on Form 8-K. Stockholders are urged not
to place undue reliance on forward-looking statements, which speak
only as of the date hereof. BioMarin is under no obligation, and
expressly disclaims any obligation to update or alter any
forward-looking statement, whether as a result of new information,
future events or otherwise.
BioMarin® is a registered trademark and
Brineura™ is a trademark of BioMarin Pharmaceutical Inc.
1 The Hamburg Motor + Language CLN2 rating is a
standardized mobility (motor) and language score using a CLN2
disease-specific rating scale. The scale separately measures
performance of mobility and language with normal function in each
being a score of 3 and no function being a score of 0. The
highest score possible is 6.
2 Nickel M, Jacoby D, Lezius S, Down M, Genter F, Wittes J,
Kohlschütter A, Schulz, A Natural history of CLN2 disease:
Quantitative assessment of disease characteristics and rate of
progression, poster presented at WORLDSymposium 2016
Contact:
Investors:
Traci McCarty
BioMarin Pharmaceutical Inc.
(415) 455-7558
Media:
Debra Charlesworth
BioMarin Pharmaceutical Inc.
(415) 455-7451
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